CC-1065 transformations

This report defines the transformations that antitumor antibiotic CC-1065 underwent under basic and acidic conditions. The isolation, purification, characterization, and biological properties of a cyclopropapyrroloindole fragment, and an acidic fragment, PDE-I dimer, from a mild alkaline fragmentation and the phenolic product, AAP, resulting from alkylation of acetic acid by the cyclopropyl function are described.     

CC-1088 Celgene

CC-1088, a thalidomide analog inhibitor of phosphodiesterase 4, was being developed by Celgene for the potential treatment of inflammatory diseases and myelodysplastic syndromes, and had undergone clinical trials. By April 2005, however, the company was no longer developing CC-1088, with CC-10004 presumed to be the preferred compound.     

CC-5013 (Celgene)

Celgene, in collaboration with the National Cancer Institute, is developing CC-5013, the lead compound in a series of thalidomide derivatives that inhibit TNFalpha overproduction, for the potential treatment of hematological and solid tumor cancers and inflammatory diseases.     

真菌CC-8810的研究——Ⅱ.孢内、孢外多糖活性成分的分离

本文报道真菌CC8810产生的孢内孢外多糖的分离纯化工艺,并对分离的三个组份做了一些理化性质测定。用0.5mol/L硫酸110℃水解6小时,纸层分析表明,组份Ⅰ含D-葡萄糖、D-木糖、L-阿拉伯糖、D-半乳糖、不含蛋白质和核苷酸。组份Ⅱ、组份Ⅲ含D-葡萄糖、D-木糖、L-阿拉伯糖、D-半乳糖和L-岩藻糖,不含核苷酸。对组份Ⅰ、Ⅱ、Ⅲ做了红外光谱分析。     

口服阿莫西林胶囊10004例不良反应观察

本文报道免做青霉素皮试口服阿莫西林１０００４例病人不良反应观察结果。所有病人口服阿莫西林的剂量为０．５ｇ,１日３次,餐后０．５ｈ服,疗程４ｄ。１０００４例患者中出现不良反应与药物有关者７１例,很可能有关者１５９例,不良反应发生率为２．３％（２３０／１０００４）。最常见的不良反应为恶心、头昏、皮疹等。试验结果显示,在服药前详细询问青霉素及其他药物过敏史、过敏性疾患史的前提下,首剂在医护人员密切观察下服药、免做青霉素皮试用于临床基本是安全的。     

CC-1065 and the duocarmycins: recent developments

It is accepted that neoplastic diseases are related to gene alteration or oncogene activation. In particular, DNA minor groove binding drugs have been extensively studied through the years in order to influence the regulation of gene expression by means of specific interactions with DNA based moieties. In this field, analogues of naturally occurring antitumour agents, such as CC-1065 and/or the duocarmycins, represent a new class of highly potent antineoplastic compounds, currently under investigation. CC-1065 and duocarmycins represent a class of exceptionally potent antitumour antibiotics that derive their biological effects from the reversible, stereo-electronically-controlled sequence selective alkylation of DNA. All natural compounds showed a cytotoxicity against leukaemia L1210 cell lines in the range 10 - 220pM but while CC-1065 showed a good antitumour activity in an in vivo model (optimal dose from 10 - 100 μg/g), duocarmycins showed weak antitumour activity. Despite its potency, CC-1065 cannot be used in humans due to eventual fatality. For this reason many scientists have focused their attention on this class of compounds, in order to obtain new derivatives with equal in vitro potency but a better profile in in vivo models. This effect is accompanied by dramatic changes in the morphology of hepatic mitochondria. On this basis, the recent developments on SARs for this class of compounds and their possible use as therapeutic agents are reviewed, with particular emphasis on recent patent literature and, finally, a conclusive opinion will be given on this topic.     

Structure and activity relationship of several novel CC-1065 analogs

Summary CC-1065 was found to cause delayed toxicity at therapeutic doses, therefore, a large number of analogs have since been synthesized. A series of analogs with simplified but closely related structures were chosen for this investigation because some were found to be superior to CC-1065 in the treatment of several experimental tumors. The inhibition of L1210 cell growth by U-68,415 was comparable to that by CC-1065. A similar situation was true in terms of their in vivo potency; however, U-68,415 was superior to CC-1065 in terms of anti-P 388 leukemia activity. At the optimal dosage, U-68,415 produced 4 out of 6 long-term (> 30 day) survivors; whereas CC-1065 produced a mere 62% increase of life span (ILS) and no long-term survivors. The order of antitumor potency and effectiveness of the CC-1065 analogs was U-68,415 > U-66,694 > U-68,819 > U-66,664, which was parallel to the inhibition of L1210 cell growth. CC-1065 and all the analogs tested here inhibited DNA synthesis approximately 10 times more than RNA synthesis. Protein synthesis was the least inhibited. On a molar basis, U-68,415 was about 6–9 times more inhibitory toward cellular DNA synthesis than CC-1065, yet the interaction and/or binding of CC-1065 to DNA determined by circular dichroism, DNA melting or differential cytotoxicity assay was much stronger than that of U-68,415. The order of binding of these analogs to calf thymus DNA was U-68,415 > U-66,694 > U-68,819 > U-66,664, and was parallel to that of DNA synthesis inhibition which was in turn parallel to cell growth inhibition and antitumor potential. These results collectively suggest that the cellular DNA is a major site of the action of CC-1065 analogs; however, time course studies reveal that the inhibition of cellular DNA synthesis could not wholly account for their cytotoxicity. Hence, the precise mechanism of action of these agents is not yet fully understood. U-68,415, which exhibited superior activity against a number of tumors and did not cause delayed death in mice, warrants further investigation. U-68,415 is a racemate and two chiral isomers were recently isolated. Therefore, further investigation of both U-68,415 and its chiral isomers is necessary.     

Biosynthesis of the antitumor antibiotic CC-1065 by Streptomyces zelensis

The biosynthesis of the antitumor antibiotic, CC-1065, has been investigated by radioactive isotope techniques, in combination with chemical degradation of CC-1065. Tyrosine, dopa, serine and methionine (S-CH3 group) have been shown to be precursors of CC-1065. Tyrosine is proposed to be a precursor of all three benzodipyrrole subunits, while dopa is only apparently incorporated into subunits B and C. Serine is postulated to contribute three 2C units, with loss of C-1, to all three subunits of CC-1065. The S-CH3 group of methionine probably contributes four C-1 units to CC-1065 of which one is incorporated with considerable loss of tritium, most probably into the cyclopropane ring of subunit A.     

Gilvusmycin, a new antitumor antibiotic related to CC-1065.

A new antitumor antibiotic gilvusmycin was isolated from the culture broth of Streptomyces sp. QM16. The structure of gilvusmycin was related to CC-1065 and determined by NMR spectral analysis. Gilvusmycin exhibited antitumor activity against murine leukemia P388 in vivo.     

LC determination of a sulphur mustard decontaminant CC-2 in rat serum

A high-performance liquid chromatographic (HPLC) method was developed for the analysis of N,N'-Dichlorobis (2,4,6-trichlorophenyl) urea (CC-2), a potent sulphur mustard decontaminant, in rat serum. The HPLC analysis, applicable to 0.5 ml volumes of serum, involved double extraction of serum samples with diethyl ether at alkaline pH followed by separation on a RP-18 column and the use of UV detector at 230 nm. The method was sensitive with a limit of quantitation of 10 ng ml(-1) in rat serum and the recovery was always >90%. Excellent linear relationships (r>0.99) were obtained between the measured and added concentration ratios of the serum concentrations over a range of 10-200 ng ml(-1). The precision and accuracy were acceptable as indicated by relative standard deviation ranging from 2.47 to 17.49%, bias values ranging from -4.35 to 13.21%. Moreover, CC-2 was found stable in rat serum even after 3 months of storage at -60 degrees C and being subjected to three freeze-thaw cycles. The assay was found to be sensitive, specific, accurate, precise, and reliable for use in pharmacokinetic studies.     

Adozelesin,a selected lead among cyclopropylpyrroloindole analogs of the DNA-binding antibiotic,CC-1065

Summary Adozelesin (U-73975) is a potent synthetic cyclopropylpyrroloindole (CPI) analog of the cytotoxic DNA-binding antibiotic, CC-1065. In contrast to the natural product, adozelesin and related CPI analogs do not cause delayed death in non-tumored mice. Adozelesin, selected from a series of analogs for its superior in vivo antitumor activity and ease of formulation, is highly active when administered i.v. against i.p.- or s.c.-implanted murine tumors, including L1210 leukemia, B16 melanoma, M5076 sarcoma, and colon 38 carcinoma, and produces long-term survivors in mice bearing i.v.-inoculated L1210 and Lewis lung carcinoma. Modest activity is shown against the highly drug-resistant pancreas 02 carcinoma. Adozelesin is also highly effective against human tumor xenografts s.c.-implanted in athymic (nude) mice, including colon CX-1 adenocarcinoma, lung LX-1 tumor, clear cell Caki-1 carcinoma, and ovarian 2780 carcinoma. Its broad spectrum of in vivo activity compares favorably with three widely used antitumor drugs, i.e. cisplatin, cyclophosphamide, and doxorubicin. Adozelesin appears to be more effective than these drugs in the treatment of very resistant tumors such as s.c.-implanted mouse B16 melanoma, pancreatic 02 carcinoma, and human colon CX-1 and human lung LX-1 tumor xenografts. Based on its high potency and high efficacy against a broad spectrum of experimental tumors, adozelesin was chosen for clinical investigation and development.     

ARDS患者血清CC-16水平及临床诊断价值研究

目的 探讨急性呼吸窘迫综合征(ARDS)患者血清Clara细胞分泌蛋白-16(clara cell protain-16,CC-16)水平及诊断ARDS的临床价值.方法 纳入2011年10月至2016年2月就诊的ARDS患者62例(ARDS组),同时纳入44例健康人作为对照(健康对照组).患者就诊时记录一般情况、检测肺功能、动脉血气分析等常规指标,酶联免疫法检测血清CC-16、脑钠肽(BNP)水平.分析CC-16与临床指标的相关性,ROC曲线考察诊断价值.结果 ARDS组CC-16水平显著高于健康对照组,差异有统计学意义[(19.89±8.59) vs.(11.04±4.77)ng/ml,P<0.01].ARDS不同严重程度患者CC-16水平由高至低为:重度ARDS组[(26.46±7.58)ng/ml]、中度ARDS组[(19.64±7.01)ng/ml]及轻度ARDS组[(12.94±6.08)ng/ml].ARDS组中,CC-16与APACHEⅡ评分(r=0.583,P<0.01)、SOFA评分(r=0.536,P<0.01)及BNP(r=0.427,P<0.01)呈显著正相关,与PaO2/FiO2(r=-0.650,P<0.01)呈显著负相关.血清CC-16水平单独用于ARDS的诊断的AUC为0.800(96%CI:0.719~0.882),联合BNP的AUC为0.834(95%CI:0.759~0.909).结论 ARDS患者CC-16水平存在显著增高,且CC-16单独或联合BNP诊断ARDS的临床价值较高.     

Stereoelectronic factors influencing the biological activity and DNA interaction of synthetic antitumor agents modeled on CC-1065

The synthesis, physicochemical properties, and biological activities of a series of novel spiro cyclopropyl compounds, modeled on the potent antitumor antibiotic CC-1065 (1), are described. Many of these synthetic analogues are significantly more effective than 1 against murine tumors. In particular, compound 27 exhibits high activity and potency. Structure-activity analysis supports a molecular mechanism for biological action involving hydrophobic interaction of the drug with DNA and acid-catalyzed alkylation of DNA.     

CC-1065 analogues bearing different DNA-binding subunits: synthesis,antitumor activity,and preliminary toxicity study

CC-1065 analogues bearing different DNA-binding subunits were synthesized. A terminal C5-NO2 and -F moiety at the DNA-binding subunit increased the drug's potency and antitumor efficacy. A C5-OCH3 reduced the potency and antitumor efficacy. Compound (+/-)-7, bearing a trans double bond, had increased antitumor efficacy. A preliminary toxicity study indicated that terminal C5-OCH3 and -acetamido moieties at the DNA-binding subunit caused delayed death in mice.     

Evaluation of protective efficacy of CC-2 formulation against topical lethal dose of T-2 toxin in mice

T-2 toxin is the type-A trichothecene and a common contaminant of food and cereals, produced by Fusarium species. T-2 toxin easily penetrates skin due to its lipophilic nature and causes skin irritation and blisters in humans. Physical protection of the skin and airway is the only proven effective method of protection. To date, no chemical antidotes are available to prevent T-2 induced lethality. In the present study, we evaluated the protective efficacy of 20% N,N′-dichloro-bis(2,4,6-trichlorophenyl) urea (CC-2) formulation against lethal topical exposure dose of T-2 toxin in mice. None of the animals exposed to only T-2 toxin at lethal dose of 2 and 4 LD50 (11.8 and 23.76 mg/kg body weight) survived beyond 36 and 16 h, respectively. CC-2 application at 5 and 15 min post-exposure protected mice 100% from lethality at 2 LD50. Survival rate was 100% and 50% at 4LD50 dose if CC-2 was applied dermally within 5 and 15 min post-exposure. Recovery profile of surviving animals after 2LD50 T-2 toxin exposure at 1, 3, 7, and 14 days was assessed in terms of hepatic GSH, lipid peroxidation, serum ALP, ALT and AST. Hepatic lipid peroxidation significantly increased in all groups exposed to T-2 toxin by 3 day but normalized by day 7. A delayed GSH depletion was noted in surviving animals on day 7 but recovered by day 14. ALT and AST levels were elevated in all CC-2 protected mice on day 1 and normalized by day 3. ALP level decreased till day 7 in all protected groups. The biochemical variables recovered to control values by 14th day. GC–MS analysis after in vitro interaction of CC-2 formulation with T-2 toxin had shown that nearly 86% of T-2 toxin is decontaminated in 5 min but 8–10% of T-2 toxin was still present even after 60 min of interaction. Results of our study suggest that CC-2 may be an effective dermal decontaminant against lethal topical exposure of T-2 toxin.     

Synthesis and preliminary biological evaluations of CC-1065 analogues: effects of different linkers and terminal amides on biological activity

CC-1065 analogues possessing a biologically active CBI functional group and amide-substituted indole and benzofuran were synthesized. The IC(50) values of compounds 26, bearing two indoles, and 25, bearing only one indole, are 0.4 and 3 nM, respectively, against U937 leukemia cells in vitro. The IC(50) values of compounds 28, bearing a butyramino group, and 27, bearing an acetamino group, are 0.008 and 0.4 nM, respectively, against U937 leukemia cells in vitro. Compound 29, bearing a double-bond linker, is about 4-fold more potent than 25, bearing no double-bond linker. Compound 26 is highly potent against all cell lines tested in the NCI in vitro screening with IC(50) values in the 0.1-5 nM range for most cell lines. Compounds 26 and 30 are highly active against L1210 leukemia in mice. Compound 26 is also active against B16BL6 melanoma in mice. Most importantly, 26 and 30 are not myelosuppressive at therapeutically effective doses. The mechanism of tumor cell death is through induction of apoptosis, and is accompanied by DNA fragmentation.     

Determination of the biological activity and structure activity relationships of drugs based on the highly cytotoxic duocarmycins and CC-1065

The natural antibiotics CC‑1065 and the duocarmycins are highly cytotoxic compounds which however are not suitable for cancer therapy due to their general toxicity. We have developed glycosidic prodrugs of seco-analogues of these antibiotics for a selective cancer therapy using conjugates of glycohydrolases and tumour-selective monoclonal antibodies for the liberation of the drugs from the prodrugs predominantly at the tumour site. For the determination of structure activity relationships of the different seco-drugs, experiments addressing their interaction with synthetic DNA were performed. Using electro­spray mass spectrometry and high performance liquid chromatography, the experiments revealed a correlation of the stability of these drugs with their cytotoxicity in cell culture investigations. Furthermore, it was shown that the drugs bind to AT-rich regions of double-stranded DNA and the more cytotoxic drugs induce DNA fragmentation at room temperature in several of the selected DNA double-strands. Finally, an explanation for the very high cytotoxicity of CC-1065, the duocarmycins and analogous drugs is given.     

Absorption,distribution, metabolism,and excretion of mTOR kinase inhibitor CC-223 in rats,dogs, and humans

1. The absorption, distribution, metabolism, and excretion of CC-223 were studied following a single oral dose of [¹⁴C]CC-223 to rats (3?mg/kg; 90 μCi/kg), dogs (1.5?mg/kg; 10 μCi/kg), and healthy volunteers (20?mg; 200 nCi).

2. CC-223-derived radioactivity was widely distributed in rats. Excretion of radioactivity was rapid and nearly complete from rats (87%), dogs (78%), and humans (97%). Feces was the major excretion pathway for rats (67%) and dogs (70%), whereas urine (57.6%) was the major elimination route for humans. Urine and bile each contained approximately 20% administered radioactivity in rats, whereas bile (20%) played a more important role than urine (<10%) in the excretion of absorbed radioactivity in dogs. Based on excretion data, CC-223 had good absorption, with greater than 56%, 29%, and 57% of the oral dose absorbed in rats, dogs, and humans, respectively.

3. CC-223 was the prominent radioactive component in circulation of rats (>71% of the exposure to total radioactivity) and dogs (≥45.5%), whereas M1 (76.5%) was the predominant circulating metabolite in humans. M1 and M1-derived metabolites accounted for?>66% of human dose. CC-223 was extensively metabolized in rats, dogs, and humans through glucuronidation, O-demethylation, oxidation, and combinations of these pathways.